Significance. The comparative effectiveness of long-acting beta agonists (LABA) in asthma management with other controller medicines has not been established. Although LABA monotherapy increases the risk of serious adverse events (AEs) and is recommended to be used in combination with inhaled corticosteroids (ICS), the safety of combination therapy is not known. Also not known, and clinically important to understand, is how, why and to whom LABAs and/or combination therapy are associated with increased risk of serious AEs. Specific Aims. To address the comparative effectiveness and safety concerns of the combination therapy (ICS + LABA), as well as to understand the profile of those who experience AE, and the profile of those who benefit most from the combination therapy, we will (1) determine the effectiveness of LABA-containing therapies in comparison with other available controller regimens in persistent asthma disease management; (2) determine if LABA-containing therapies are associated with an increased risk of asthma-related serious AEs and all-cause mortality; and (3) determine the characteristics of patients who clinically respond to, or have AEs attributable to, LABA-containing therapies. Research Design. In Aim 1, we will conduct a population based cohort study of subjects with persistent asthma. The effect of LABA-containing therapies in the real-world setting will be measured and compared with other asthma controller therapies on asthma control and exacerbation prevention from 1998-2010. This period allows for the study of LABAs during use of LABA monotherapy, and during a period prior to AE recognition and the FDA black box warning. The study will be done in diverse populations of nearly 664,000 asthmatics which we have assembled, including a state Medicaid population, four HMO research populations, and a Department of Defense population. In Aim 2, we will conduct a nested case-control study to evaluate the risk of serious asthma-related AEs with the use of LABA-containing therapies. Asthma-related and all-cause death will be studied separately. In Aim 3, patient characteristics associated with both response to, and serious AEs related to, LABA-containing therapies will be assessed, including patient demographics, disease severity, underlying asthma control, medication utilization patterns, adherence, and definable asthma phenotypes using multivariable regression modeling. For each aim, various subgroup analyses, sensitivity analyses and simulation studies will be performed to provide robust results and to evaluate the accuracy of the estimates. Impact. This project is of critical importance as it addresses comparative effectiveness and safety concerns in asthma pharmacotherapy. It will inform and empower physicians, patients, and healthcare policy makers providing timely knowledge in how, when, and to whom to provide or avoid LABA containing therapies. Such knowledge will have widespread public health impact in asthma disease management.